Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, United Kingdom.
Handb Clin Neurol. 2024;203:69-88. doi: 10.1016/B978-0-323-90820-7.00013-6.
The neuromuscular junction is a prototypic synapse that has been extensively studied and provides a model for smaller and less accessible central synapses. Central to transmission at the neuromuscular synapse is the muscle acetylcholine receptor cation channel. Studies of the genetic disorders affecting the neuromuscular junction, termed congenital myasthenic syndromes, have illustrated how impaired signal transmission may be caused by a variety of mutations both within the ion channel itself and by the context of the ion channel within the synapse. Thus, multiple pathogenic mutations are also identified in proteins affecting the clustering, location, and density of the receptor within the overall synaptic structure. Disease severity ranges from death in childhood to mild disability throughout life. In addition, in utero, fetal akinesia due to impaired neuromuscular transmission may cause developmental abnormalities. Early studies identified mutations in the genes encoding the acetylcholine receptor subunits that impair ion channel gating or reduce the number of endplate receptors or a combination of the two, giving rise to "slow channel," "fast channel," or deficiency syndromes. Subsequently, it became clear that myasthenic syndromes also stem from mutations in proteins involved in neurotransmitter release, the formation and maintenance of the neuromuscular synapse, or glycosylation. This chapter describes the patient phenotypes, the diverse range of molecular mechanisms for synaptic dysfunction, and the corresponding therapeutic strategies, including drug combinations, that can be tailored to the many subtypes.
神经肌肉接头是一种典型的突触，已经得到了广泛的研究，为较小且难以接近的中枢突触提供了模型。在神经肌肉突触的传递中，肌肉乙酰胆碱受体阳离子通道是核心。对影响神经肌肉接头的遗传疾病（称为先天性肌无力综合征）的研究表明，信号传递的障碍可能是由离子通道本身的各种突变以及离子通道在突触中的环境引起的。因此，在影响受体在整个突触结构中的聚集、位置和密度的蛋白中也发现了多种致病突变。疾病的严重程度范围从儿童期死亡到终身轻度残疾。此外，在子宫内，由于神经肌肉传递受损导致的胎儿运动不能可能会导致发育异常。早期的研究确定了编码乙酰胆碱受体亚基的基因突变，这些突变会损害离子通道门控或减少终板受体的数量，或者两者兼而有之，从而导致“慢通道”、“快通道”或缺乏综合征。随后，人们清楚地认识到肌无力综合征也源自涉及神经递质释放、神经肌肉突触形成和维持或糖基化的蛋白中的突变。这一章描述了患者的表型、突触功能障碍的多种分子机制以及相应的治疗策略，包括可以针对许多亚型进行定制的药物组合。
